-
1.
Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study
de Masson, A., Beylot-Barry, M., Ram-Wolff, C., Mear, J. B., Dalle, S., d'Incan, M., Ingen-Housz-Oro, S., Orvain, C., Abraham, J., Dereure, O., et al
Lancet (London, England). 2023
-
-
-
Full text
-
Editor's Choice
Abstract
BACKGROUND Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. METHODS In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18-70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. FINDINGS From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. INTERPRETATION Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. FUNDING French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.
PICO Summary
Population
Adults with advanced cutaneous T-cell lymphomas from 17 centres in France (n=99)
Intervention
Participants with an available donor receiving allogeneic HSCT (n=55)
Comparison
Participants without an available donor, undergoing non-HSCT therapy (n=44)
Outcome
The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group.
-
2.
Cord blood transplantation for adult lymphoid neoplasms in Europe and Japan
Watanabe, M., Kanda, J., Volt, F., Ruggeri, A., Suzuki, R., Rafii-Elayoubi, H., Kimura, F., Cappelli, B., Kondo, E., Scigliuolo, G. M., et al
Blood advances. 2023
Abstract
With the aim of identifying the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study between European and Japanese registries. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n=192; double CBT, n=304; Japan: single CBT, n=1150) in 2000-2017 were analyzed. The number of patients with Hodgkin's lymphoma was higher in Europe (26% vs 5%) while that with mature T/NK-cell neoplasms was higher in Japan (20% vs 35%). The Japanese cohort comprised more elderly patients (>=50) (59% vs 39%) with higher refined disease risk index (rDRI) (high-very high: 49% vs 14%). High-very high rDRI (vs. low rDRI) was associated with inferior OS in common (Europe: HR 1.87 p=0.001; Japan: HR 2.34, p<0.001) with higher progression/relapse risks (Europe: HR 2.04, p=0.007; Japan: HR 2.96, p<0.001). Total body irradiation (TBI)-containing conditioning regimens contributed to superior OS both in Europe (vs TBI-RIC, non TBI-RIC: HR 1.93, p<0.001; non TBI-MAC: HR 1.90, p=0.003) and in Japan (non TBI-RIC: HR 1.71, p<0.001; non TBI-MAC: HR 1.50, p=0.007). The impact of HLA mismatches (>=2) on OS differed (Europe: HR 1.52, p=0.007; Japan: HR 1.18, p=0.107). Despite the different patient-disease-transplant characteristics, poor survival of patients receiving CBT for lymphoid neoplasms, especially in those with high rDRI was observed in both registries. The different impact of HLA mismatches on survival in the two registries calls attention to the fundamental differences among these populations. TBI should be considered in conditioning regimens.
-
3.
Immune landscape after allo-HSCT: TIGIT and CD161-expressing CD4 T cells are associated with subsequent leukemia relapse
Gournay, V., Vallet, N., Peux, V., Vera, K., Bordenave, J., Lambert, M., Corneau, A., Michonneau, D., Peffault de Latour, R., Caillat-Zucman, S., et al
Blood. 2022
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the most effective treatment for selected patients with acute myeloid leukemia (AML) and relies on a "graft-versus-leukemia" effect (GVL) where donor T lymphocytes mediate control of malignant cell growth. However, relapse remains the major cause of death after allo-HSCT. In various malignancies, several immunoregulatory mechanisms have been shown to restrain antitumor immunity, including ligand-mediated engagement of inhibitory receptors on effector cells, and induction of immunosuppressive cell-subsets such as regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). While relapse after HSCT remains a major therapeutic challenge, immunoregulatory mechanisms involved in restraining the GVL effect need to be better deciphered in humans. We used mass cytometry to comprehensively characterize circulating leukocytes in two cohorts of patients after allo-HSCT. We first longitudinally assessed various immunoregulatory parameters highlighting specific trends, such as opposite dynamics between MDSCs and Tregs. More generally, the immune landscape was rather stable from month-3 to 6, while many variations occurred from month-6 to 12 post-HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1-year post-HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 post-HSCT were distinct features significantly associated with subsequent AML relapse in a second cross sectional cohort. Altogether, these data provide global insights into the immunoregulatory landscape reconstitution following HSCT, and highlight non-canonical inhibitory receptors associated with relapse, which could open the path towards new prognostic tools or therapeutic targets to restore subverted anti-AML immunity.
PICO Summary
Population
Adults with acute myeloid leukaemia or myelodysplastic syndrome, undergoing allogeneic transplant
Intervention
Measurement of peripheral blood mononuclear cells at months 3, 6 and 12 after transplant (n=37)
Comparison
Comparison cohort of healthy volunteers (n=20)
Outcome
More generally, the immune landscape was rather stable from month-3 to 6, while many variations occurred from month-6 to 12 post-HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1-year post-HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 post-HSCT were distinct features significantly associated with subsequent AML relapse in a second cross sectional cohort.
-
4.
Hematopoietic stem cell transplantation for acute lymphoblastic leukemia: why do adolescents and young adults outcomes differ from those of children? A retrospective study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)
Grain, A., Rialland-Battisti, F., Chevallier, P., Blin, N., Dalle, J. H., Michel, G., Dhédin, N., Peffault de Latour, R., Pochon, C., Yakoub-Agha, I., et al
Journal of cancer research and clinical oncology. 2022
Abstract
PURPOSE In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences. METHOD 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts. RESULTS Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA. CONCLUSION AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.
-
5.
Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial
Beelen, D. W., Trenschel, R., Stelljes, M., Groth, C., Masszi, T., Remenyi, P., Wagner-Drouet, E. M., Hauptrock, B., Dreger, P., Luft, T., et al
The Lancet. Haematology. 2019
-
-
-
Full text
-
Editor's Choice
Abstract
BACKGROUND Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. METHODS We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m(2) treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0.8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m(2) intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1.3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15.4 months (IQR 8.8-23.6) for patients treated with treosulfan and 17.4 months (6.3-23.4) for those treated with busulfan. 2-year event-free survival was 64.0% (95% CI 56.0-70.9) in the treosulfan group and 50.4% (42.8-57.5) in the busulfan group (HR 0.65 [95% CI 0.47-0.90]; p<0.0001 for non-inferiority, p=0.0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING medac GmbH.
PICO Summary
Population
Patients with acute myeloid leukaemia in first or consecutive complete haematological remission or myelodysplastic syndrome considered at an increased risk for standard myeloablative preparative regimens based on age (>/=50 years), an HSCT-specific comorbidity index of more than 2, or both. (n=460)
Intervention
Intravenous 10 g/m(2) treosulfan daily for 3 days followed by intravenous fludarabine daily for 5 days (n=221)
Comparison
0.8 mg/kg busulfan at 6-h intervals on days -4 and -3, followed by 30 mg/m(2) intravenous fludarabine daily for 5 days (n=240)
Outcome
Median follow-up was 15.4 months for patients treated with treosulfan and 17.4 months for those treated with busulfan. 2-year event-free survival was 64.0% in the treosulfan group and 50.4% in the busulfan group. The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (15% patients in the treosulfan group vs 15% in the busulfan group) and gastrointestinal disorders (11% patients vs 16% patients). Serious adverse events were reported for 8% of patients in the treosulfan group and 7% of patients in the busulfan group. Causes of deaths were generally transplantation-related.
-
6.
Alemtuzumab versus anti-thymocyte globulin in patients transplanted from an unrelated donor after a reduced intensity conditioning
Robin, M., Raj, K., Chevret, S., Gauthier, J., de Lavallade, H., Michonneau, D., McLornan, D., Peffault de Latour, R., Potter, V., Kulasekararaj, A., et al
European journal of haematology. 2018
Abstract
OBJECTIVE Relapse and graft-versus-host disease are still the main complications after allogeneic hematopoietic stem cell transplantation, especially in the setting of reduced intensity regimen (RIC) and unrelated donor. We compared here anti-thymocyte globulin (ATG) or alemtuzumab as GVHD prophylaxis in patients with myeloid disease transplanted after RIC and from an unrelated donor. METHOD ATG- and alemtuzumab -patients have been matched by age, gender, HLA matching, comorbidities and cytogenetics risk (119 patients in each group). RESULTS After matching, we found that ATG decreased the risk of relapse (HR: 0.55, p=0.0049) and improved relapse-free survival (RFS, HR: 0.70, p=0.042). The improved RFS with ATG was more pronounced in CMV positive patients but was not influenced by disease risk. Regarding overall survival, GVHD-free relapse free survival and transplant-related mortality, the risk was similar using ATG or alemtuzumab. CONCLUSION Even if GVHD risk is lowered by alemtuzumab use, it does not translate in better outcome due to higher risk of relapse. This article is protected by copyright. All rights reserved.
-
7.
Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy
Gauthier, J., Castagna, L., Garnier, F., Guillaume, T., Socie, G., Maury, S., Maillard, N., Tabrizi, R., Marchand, T., Malfuson, J., et al
Bone Marrow Transplantation. 2017;52(5):689-696
Abstract
Allogeneic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin lymphoma (HL). When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB. Ninety-eight patients were included. Median follow-up was 31 months for the whole cohort. All patients in the HAPLO group (N=34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, N=31, 91%) or a RIC (N=3, 9%) followed by post-transplant cyclophosphamide. After adjustment for significant covariates, MMUD and CB were associated with significantly lower GvHD-free relapse-free survival (GRFS; hazard ratio (HR)=2.02, P=0.03 and HR=2.43, P=0.009, respectively) compared with HAPLO donors. In conclusion, higher GRFS was observed in Hodgkin lymphoma patients receiving a RIC or NMA allo-SCT with post-transplant cyclophosphamide from HAPLO donors. Our findings suggest they should be favoured over MMUD and CB in this setting.
-
8.
Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Societe Francophone de Greffe de Moelle et de Therapie Cellulaire
Decroocq, J., Itzykson, R., Vigouroux, S., Michallet, M., Yakoub-Agha, I., Huynh, A., Beckerich, F., Suarez, F., Chevallier, P., Nguyen-Quoc, S., et al
American Journal of Hematology. 2017
Abstract
Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18-50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty-eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow-up of 48 months, 2-year overall survival was 39%, 95% confidence interval (CI) (24-53) in the myeloablative group versus 33%, 95% CI (21-45) in the sequential groups (p=0.39), and 2-year cumulative incidence of relapse was 57% versus 50% respectively (p=0.99). Non-relapse mortality was not higher in the myeloablative group (17% versus 15%, p=0.44). In multivariate analysis, overall survival, cumulative incidence of relapse and non-relapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II-IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21-0.65; p<0.001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant. This article is protected by copyright. All rights reserved.
-
9.
Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Societe Francophone de Greffe de Moelle et de Therapie Cellulaire
Le Bourgeois, A., Labopin, M., Blaise, D., Ceballos, P., Vigouroux, S., Peffault de Latour, R., Marcais, A., Bulabois, C. E., Bay, J. O., Chantepie, S., et al
Annals of Oncology. 2017;28(9):2191-2198
Abstract
Background: Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet. Patients and methods: This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4mg/kg/day oral or 3.2mg/kg/day i.v.) (n=277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4mg/kg/day oral or 3.2mg/kg/day i.v.) (n=101). Results: In univariate analysis, the 2-year overall survival (FB266.5% versus 60.3%, P=0.33), lymphoma-free survival (FB257.9% versus 49.8%, P=0.26), and non-relapse mortality (FB219% versus 21.1%, P=0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB211.2% versus 18%, P=0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P=0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P=0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P=0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P=0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P=0.07). These results were confirmed using a propensity score-matching strategy. Conclusion: We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo-SCT for NHL.
-
10.
Allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning regimen for elderly patients (60 years and older) with hematologic malignancies using unrelated donors: a retrospective study from the French society for stem cell transplantation (SFGM-TC)
El Cheikh, J., Sfumato, P., Sobh, M., Fegueux, N., Mohty, M., Vigouroux, S., Beguin, Y., Yakoub-Agha, I., Socie, G., Cornillon, J., et al
Haematologica. 2016;101(6):e262-5